Embyronic stem cells could be the key to future drug testing, replacing animal testing with a cheaper and more reliable method, writes Katie Pickup.
Patient safety is essential when testing a new drug. Drugs must also be safe for a developing embryo, since millions of people may be pregnant while on medication. Before drugs reach human clinical trials, they are screened for potential embryonic toxicity, using pregnant animals or human embryos donated from in vitro fertilisation.
Both methods are costly, and use of these resources is tightly regulated due to ethical concerns. However, promising scientific advances mean future drugs could be tested on synthetic embryo-like structures grown entirely from stem cells in a lab. This would allow for rigorous screening without the need for animal testing.
A “gastruloid” is like a synthetic embryo – under a normal white light, green fluorescence shows proteins only expressed in the “tail” end of a mouse embryo at the equivalent stage.
The Thalidomide Tragedy
In the 1960s, tragedy surrounding a drug called thalidomide brought to light the devastating effects of embryonic toxicity.
Thalidomide was prescribed for morning sickness, and unforeseen effects on foetal development led to a range of disabilities in over 10,000 babies, many of whom died in infancy. It took five years to be withdrawn from the market and the slow response led to several court cases.
Drug testing is more thorough now, yet there are unexpected quirks about thalidomide that helped it slip through the regulatory net. Any initial drug screening for thalidomide would have used mice. They are useful for studying human development and disease as we share many similarities in physiology and genetics.
Sixty years ago, treating pregnant mice with a drug and recording the health of their pups was considered a reliable method of detecting birth defects. Often, results in mice reflect those seen in humans. Not so with thalidomide. The adverse effects on limb formation are species-specific: safe for mice, tragically not for humans.
Minimising Animal Testing
Nowadays, a drug’s effect on pregnancy must be tested on multiple species, including primates. Such testing is commonly considered unethical due to potential harm inflicted on animals.
UK government-funded animal research is required to adhere to a principle of “Three Rs”: replacement, reduction, and refinement. This means researchers should avoid using animals where feasible and, if not, use as few as possible to minimise suffering.
This is where embryonic stem cells come in. These cells form in the embryo during the first week following fertilisation and can develop into any of the billions of extraordinary cells making up the adult body.
Embryonic stem cells have the ability to self-renew almost indefinitely. Human stem cells can be isolated from embryos donated by patients undergoing in vitro fertility treatments, and, because of their self-renewal capacity, a vast amount of cells can be grown from a single source.
Scientists have recently been able to exploit stem cells’ spectacular property to become any tissue in the body by encouraging them to form lab-grown structures resembling early embryos. Though they only grow in culture for around a week, these gastruloids have structures resembling early tissue, such as muscle and gut, therefore providing a fascinating insight into the early stages of development. Gastruloids generated from mouse and human stem cells hold huge potential for making human-specific predictions without the need for real embryos.
Could gastruloids have prevented the thalidomide disaster?
An innovative new study by Dr Naomi Moris and colleagues examined the effects of various drugs on human and mouse gastruloids. Many of the drugs were known to be toxic to both embryos, and indeed both gastruloids failed to develop on exposure to these drugs.
The researchers also tested thalidomide and found it had very little effect on mouse gastruloids but profoundly hindered the development of human gastruloids. Had this technology been around in the 1960s, these results could have been enough to trigger further investigation into thalidomide before prescribing it to anyone pregnant, potentially saving countless lives.
Testing drugs on gastruloids is yet to be adopted by pharmaceutical companies, but the ability to spot human-specific effects without requiring real embryos or animal testing holds huge potential in the drug screening process. As well as being more ethically sound, it’s considerably cheaper and more efficient than animal studies.
Gastruloids can be generated hundreds at a time, improving statistical power while using minimal resources. With increasing pressure from animal rights groups and the general public to reduce dependence on animals in research, these simple yet fascinating clusters of stem cells could pave the way to prevent another thalidomide-like disaster.
Katie Pickup (she/her) is a 2nd-year PhD student specialising in genetics and molecular medicine.